Expert Examines Nuances of Switching Therapies in Progressive EGFR-Positive NSCLC

Geoffrey R. Oxnard, MD

Patience is a virtue when it comes to deciding whether to switch therapies for individuals with metastatic non—small cell lung cancer (NSCLC) who appear to be progressing on an EGFR-targeting regimen, according to Geoffrey R. Oxnard, MD, a Dana-Farber Cancer Institute researcher who has made resistance mechanisms a focus of his work.

Although patients typically develop resistance after taking an EGFR tyrosine kinase inhibitor (TKI) for a median of 9 to 14 months, the matter of when to change therapy is a “nuanced question” complicated by the heterogeneous nature of progression, Oxnard said, who also is an assistant professor at Harvard Medical School.

“How do we know when a patient has developed ‘treatment failure?’” Oxnard said during a presentation at the 10th Annual New York Lung Cancer Symposium.

Typically, clinicians would consider that a patient is failing treatment if he or she is complaining of or developing toxicities from the existing regimen, exhibits new cancer-related symptoms, or shows signs of further progression such as new sites of metastasis or rapid tumor growth, Oxnard said.

Those broad criteria, however, may not provide an answer for patients with NSCLC on anti-EGFR therapy. Oxnard and colleagues conducted a retrospective study of 92 patients who had received first-line erlotinib in clinical trials and experienced progressive disease as defined by RECIST criteria.¹ They found that among 42 patients with an EGFR-sensitizing mutation, 21 (50%) were able to delay a change in systemic therapy for greater than 3 months.

A personalized approach should be used to determine the next steps for this patient population, Oxnard said. The choices including continuing TKI therapy, palliative radiation to the brain or bone if appropriate, thoracentesis/pleural catheter, or possibly a wedge resection or stereotactic body radiation therapy.

Oxnard said he considers changing therapies under these circumstances: (1) new metastatic sites of disease such as the development of brain or liver metastases; (2) cancer-related symptoms such as pain, cough, or dyspnea; (3) rapid growth of tumor burden including the risk of impending symptoms; (4) the availability of a “compelling” targeted therapy that may provide a greater benefit than chemotherapy.

He also advised clinicians to consider a rebiopsy of the tumor to determine whether analyzing the mechanisms of acquired resistance would lead to an actionable finding. He said rebiopsy results may yield “clinically relevant” findings such as the EGFR T790M resistance mutation, MET amplification, or transformation to small cell lung cancer. Other aberrations such as HER2 amplification and BRAF V600E mutations are “biologically interesting” but have not yet been translated to clinical practice in NSCLC.

Among approximately 1 in 20 patients, EGFR-mutant NSCLC will transform into small cell lung cancer with an EGFR mutation, Oxnard indicated. He said these patients are candidates for chemotherapy upon progression, with reports of responses to platinum/etoposide therapy.

The emergence of the T790M resistance mutation to anti-EGFR therapy is far more common. This mutation has been detected in 50% to 60% of rebiopsies, and its presence confers a relatively favorable prognosis compared with patients whose tumors are T790M negative.²

“Such patients are ideal candidates for clinical trials,” commented Oxnard.

Researchers are currently designing therapies to attack the EGFR T790M mutation. The most advanced agents in terms of clinical development are rociletinib (CO-1686) and osimertinib (AZD9291). The FDA has granted a priority review to both agents for patients with NSCLC with the T790M mutation following prior administration of an EGFR TKI.

Oxnard said that rebiopsy of patients with acquired resistance has proved to be feasible but that plasma-based genotyping with cell free DNA “has the potential to replace some rebiopsies.” Two methods currently available are use either digital polymerase chain reaction or next-generation sequencing.

Researchers also are studying ways to target MET-mediated resistance, which is believed to occur in 10% to 20% of cases, Oxnard said. He is leading the TATTON trial, a phase Ib study that is seeking to determine whether combining TKIs that target EGFR and MET would be an effective strategy.³ One facet of the multiarm trial is evaluating osimertinib plus the MET inhibitor savolitinib (AZD6094).

Beyond the investigational therapies currently in the works, standard-of-care chemotherapy offers a viable option, Oxnard indicated. He pointed to the results of the IMPRESS trial, which he said was the first phase III trial for patients with acquired resistance to anti-EGFR therapy.⁴ The trial evaluated cisplatin plus pemetrexed with or without gefitinib in 265 patients with EGFR mutation-positive disease who had progressed on gefitinib.

The trial found that continuing gefitinib in addition to chemotherapy did not confer a statistically significant advantage in progression-free survival. Overall response rate was approximately 32% in the gefitinib arm compared with about 34% for chemotherapy alone.

“The lesson here is chemo works,” said Oxnard. “… It is a good therapy for our patients with acquired resistance.”

Although patients may clamor for a new regimen, particularly if they have heard about emerging immunotherapies, platinum doublet remains the standard of care for T790M-negative resistance, Oxnard noted. “We shouldn’t withhold that from patients because they’re desperate for something different,” he said.

References

1. Lo PC, Dahlberg SE, Nishino M, et al. Delay of treatment change after objective progression on first-line erlotinib in epidermal growth factor receptor-mutant lung cancer. Cancer. 2015;121(15):2570-2577.
2. Oxnard GE, Arcila ME, Sima CS, et al. Acquired resistance to EGFR tyrosine kinase inhibitors in EGFR mutant lung cancer: Distinct natural history of patients with tumors harboring the T790M mutation. Clin Cancer Res. 2011;17(6):1616-1622.
3. Oxnard GE, Ramalingam SS, Ahn MJ, et al. Preliminary results of TATTON, a multi-arm phase Ib trial of AZD9291 combined with MEDI4736, AZD6094 or selumetinib in EGFR-mutant lung cancer. J Clin Oncol. 2015;33(suppl; abstr 2509).
4. Mok TS, Wu Y, Nakagawa K, et al. Gefitinib/chemotherapy vs chemotherapy in epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) after progression on first-line gefitinib: the phase III, randomized IMPRESS study. Presented at: ESMO 2014; September 26-30, 2014; Madrid, Spain. LBA2_PR.

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